Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA A receptors, which are members of the ligand-gated ion channel superfamily and (2) GABA B receptors, which are members of the G-protein linked receptor family. The GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of xcex1, xcex2 and xcex3 subunits.
Presently a total number of 21 subunits of the GABA A receptor have been cloned and sequenced. Three types of subunits (xcex1, xcex2 and xcex3) are required for the construction of recombinant GABA A receptors which most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA A receptors obtained from mammalian brain cells. There is strong evidence that the benzodiazepine binding site lies between the xcex1 and xcex3 subunits. Among the recombinant GABA A receptors, xcex11xcex22xcex32 mimics many effects of the classical type-I BzR subtypes, whereas xcex12xcex22xcex32, xcex13xcex22xcex32 and xcex15xcex22xcex32 ion channels are termed type-II BzR.
It has been shown by McNamara and Skelton in Psychobiology, 21:101-108 that the benzodiazepine receptor inverse agonist xcex2-CCM enhance spatial learning in the Morris watermaze. However, xcex2-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans. In addition, these compounds are non-selective within the GABA A receptor subunits, whereas a GABA A xcex15 receptor partial or full inverse agonist which is relatively free of activity at GABA A xcex11 and/or xcex12 and/or xcex13 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity. It is also possible to use GABA A xcex15 inverse agonists which are not free of activity at GABA A xcex11 and/or xcex12 and/or xcex13 receptor binding sites but which are functionally selective for xcex15 containing subunits. However, inverse agonists which are selective for GABA A xcex15 subunits and are relatively free of activity at GABA A xcex11, xcex12 and xcex13 receptor binding sites are preferred.
The present invention is concerned with substituted imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine derivatives of the following formula 
wherein
R1 is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, trifluoromethyl, trifluoromethoxy or lower alkylthio;
R2 is xe2x80x94C(O)O-lower alkyl, unsubstituted isoxazol, 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl, or isoxazol, 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl, substituted by lower alkyl, trifluoromethyl or cycloalkyl;
R3 is hydrogen, lower alkyl, xe2x80x94(CH2)n-cycloalkyl, xe2x80x94(CH2)n-halogen, xe2x80x94(CH2)n-pyridin-4-yl, or unsubstituted xe2x80x94(CH2)n-phenyl, or xe2x80x94(CH2)n-phenyl substituted by one or two substituents selected from the group consisting of lower alkoxy, halogen, xe2x80x94SO2CH3, phenyl, OCF3, nitro, CF3, xe2x80x94NR2, or is unsubstituted xe2x80x94(CH2)n-indolyl, -or xe2x80x94(CH2)n-indolyl substituted by lower alkyl or lower alkoxy, or is pyrrolidinyl-5-oxo, xe2x80x94C(O)xe2x80x94NR2, xe2x80x94(CH2)nxe2x80x94OH, xe2x80x94(CH2)nxe2x80x94NR2 or xe2x80x94(CH2)n-benzo[1,3]dioxole;
R is hydrogen or lower alkyl; and
n is 0, 1, 2 or 3;
or a pharmaceutically acceptable acid addition salt thereof with the exception of the following compounds:
A.) Ethyl 9H-imidazo[1,5-a][1,2,4]triazolo[3,4-d][1,4]benzodiazepine-10-carboxylate,
B.) 10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,
C.) ethyl 3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylate,
D.) 10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-3-fluoro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine,
E.) ethyl 3-chloro-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylate or
F.) 3-chloro-10-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]benzodiazepine.
The above mentioned specific (A-F) imidazo[1,5-a][1,2,4]triazolo-[4,3-d][1,4]benzodiazepine derivatives have already been described (Heterocycles, Vol. 39, No. 2, 1994), however, in this document it is mentioned that these compounds unexpectedly show low affinities for BzR (benzodiazepine receptor) and therefore are devoid of anxiolytic activity. Surprisingly, it has now been found that this class of compounds show high affinity and selectivity for GABA A xcex15 receptor binding sites indicative of utility as cognitive enhancer or for the treatment of cognitive disorders like Alzheimer""s disease.
Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
The most preferred indication in accordance with the present invention is Alzheimer""s disease.